Paediatric, maternal, and congenital mpox: a systematic review and meta-analysis.

BACKGROUND: Although mpox has been detected in paediatric populations in central and west Africa for decades, evidence synthesis on paediatric, maternal, and congenital mpox, and the use of vaccines and therapeutics in these groups, is lacking. A systematic review is therefore indicated to set the research agenda. METHODS: We conducted a systematic review and meta-analysis, searching articles in Embase, Global Health, MEDLINE, CINAHL, Web of Science, Scopus, SciELO, and WHO databases from inception to April 17, 2023. We included studies reporting primary data on at least one case of confirmed, suspected, or probable paediatric, maternal, or congenital mpox in humans or the use of third-generation smallpox or mpox vaccines, targeted antivirals, or immune therapies in at least one case in our population of interest. We included clinical trials and observational studies in humans and excluded reviews, commentaries, and grey literature. A pooled estimate of the paediatric case fatality ratio was obtained using random-effects meta-analysis. This study is registered with PROSPERO (CRD420223336648). FINDINGS: Of the 61 studies, 53 reported paediatric outcomes (n=2123 cases), seven reported maternal or congenital outcomes (n=32 cases), two reported vaccine safety (n=28 recipients), and three reported transmission during breastfeeding (n=4 cases). While a subset of seven observational studies (21 children and 12 pregnant individuals) reported uneventful treatment with tecovirimat, there were no randomised trials reporting safety or efficacy for any therapeutic agent. Among children, the commonest clinical features included rash (86 [100%] of 86), fever (63 [73%] of 86), and lymphadenopathy (40 [47%] of 86). Among pregnant individuals, rash was reported in 23 (100%) of 23; fever and lymphadenopathy were less common (six [26%] and three [13%] of 23, respectively). Most paediatric complications (12 [60%] of 20) arose from secondary bacterial infections. The pooled paediatric case fatality ratio was 11% (95% CI 4-20), I2=75%. Data from 12 pregnancies showed half resulted in fetal death. Research on vaccine and immune globulin safety remains scarce for children and absent for pregnant individuals. INTERPRETATION: Our review highlights critical knowledge gaps in the epidemiology, prevention, and treatment of mpox in children and pregnant individuals, especially those residing in endemic countries. Increased funding, international collaboration, and equitable research is needed to inform mpox control strategies tailored for at-risk communities in endemic countries. FUNDING: None. TRANSLATIONS: For the French, Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Neuroinflammation, autoinflammation, splenomegaly and anemia caused by bi-allelic mutations in IRAK4.

We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic mutations in IRAK4. IRAK-4 is a serine/threonine kinase with a pivotal role in innate immune signaling from toll-like receptors and production of pro-inflammatory cytokines. In humans, bi-allelic mutations in IRAK4 result in IRAK-4 deficiency and increased susceptibility to pyogenic bacterial infections, but autoinflammation has never been described. We describe 5 affected patients from 2 unrelated families with compound heterozygous mutations in IRAK4 (c.C877T (p.Q293*)/c.G958T (p.D320Y); and c.A86C (p.Q29P)/c.161 + 1G>A) resulting in severe systemic autoinflammation, massive splenomegaly and severe transfusion dependent anemia and, in 3/5 cases, severe neuroinflammation and seizures. IRAK-4 protein expression was reduced in peripheral blood mononuclear cells (PBMC) in affected patients. Immunological analysis demonstrated elevated serum tumor necrosis factor (TNF), interleukin (IL) 1 beta (IL-1ß), IL-6, IL-8, interferon α2a (IFN-α2a), and interferon ß (IFN-ß); and elevated cerebrospinal fluid (CSF) IL-6 without elevation of CSF IFN-α despite perturbed interferon gene signature. Mutations were located within the death domain (DD; p.Q29P and splice site mutation c.161 + 1G>A) and kinase domain (p.Q293*/p.D320Y) of IRAK-4. Structure-based modeling of the DD mutation p.Q29P showed alteration in the alignment of a loop within the DD with loss of contact distance and hydrogen bond interactions with IRAK-1/2 within the myddosome complex. The kinase domain mutation p.D320Y was predicted to stabilize interactions within the kinase active site. While precise mechanisms of autoinflammation in NASA remain uncertain, we speculate that loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production. Blockade of IL-6 resulted in immediate and complete amelioration of systemic autoinflammation and anemia in all 5 patients treated; however, neuroinflammation has, so far proven recalcitrant to IL-6 blockade and the janus kinase (JAK) inhibitor baricitinib, likely due to lack of central nervous system penetration of both drugs. We therefore highlight that bi-allelic mutation in IRAK4 may be associated with a severe and complex autoinflammatory and neuroinflammatory phenotype that we have called NASA (neuroinflammation, autoinflammation, splenomegaly and anemia), in addition to immunodeficiency in humans.

Availability and use of rapid diagnostic tests for the management of acute childhood infections in Europe: A cross-sectional survey of paediatricians.

BACKGROUND: Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability. METHODS AND FINDINGS: A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics. CONCLUSION: There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicians, and the role of diagnostic tests in the management of acute childhood infections.

Mesangiocapillary glomerulonephritis complicating pulmonary tuberculosis.

Glomerulonephritis in tuberculosis may be a direct manifestation of renal infection or a result of immune-complex deposition complicating extra-renal infection, such as in pulmonary tuberculosis. A 17-year-old adolescent boy from Somalia was found to have pulmonary tuberculosis during routine health screening performed on entering Malta, with computed tomography of the chest showing scarring and calcification of the left upper lobe, left lower lobe consolidation, and a small left-sided pleural effusion. Five days after starting anti-tuberculous therapy, he developed lower limb and sacral oedema: urinary albumin: creatinine ratio was > 400 µg albumin/mg creatinine, and 24-h urinary protein showed nephrotic-range proteinuria of 4.963 g/day. In view of worsening lower limb, sacral and periorbital oedema and ascites, he was started on oral prednisolone, omeprazole and penicillin V prophylaxis. As heavy proteinuria persisted, a renal biopsy was performed after 8 days of prednisolone treatment, which confirmed the presence of mesangiocapillary glomerulonephritis (MCGN), with electron microscopy showing effacement of the podocytes, with hypercellularity and subendothelial immune deposits, confirming an immune-mediated pathophysiology. Ziehl-Neelsen staining did not reveal acid-fast organisms. The patient received a total of 3 weeks of oral prednisolone with subsequent tailing doses, 2 months of pyrazinamide and ethambutol and 6 months of rifampicin and isoniazid with complete resolution of his clinical and radiological signs, though heavy proteinuria persisted, so he was commenced on oral enalapril. This case highlights the potential association of MCGN with tuberculosis in adolescence. Timely recognition and treatment can prevent progression to chronic kidney disease.

Meropenem-induced thrombocytopenia: a paediatric case.

Meropenem is a broad-spectrum carbapenem widely used to treat both Gram-positive and negative bacterial infections, including extended-spectrum beta-lactamase-producing microbes. We describe the occurrence of thrombocytopenia and hypersensitivity in a boy receiving intravenous meropenem for intra-abdominal sepsis secondary to perforated appendicitis. The patient developed a pruritic maculopapular rash with occasional petechiae, associated with severe thrombocytopenia, after 7 days of meropenem administration. Investigations for other causes of thrombocytopenia, including possible line sepsis, were unfruitful, and the thrombocytopenia did not resolve until cessation of meropenem. Drug-induced reactions should be considered in children receiving meropenem who present with a rash and thrombocytopenia.

Genomic analysis of the meningococcal ST-4821 complex-Western clade, potential sexual transmission and predicted antibiotic susceptibility and vaccine coverage.

INTRODUCTION: The ST-4821 complex (cc4821) is a leading cause of serogroup C and serogroup B invasive meningococcal disease in China where diverse strains in two phylogenetic groups (groups 1 and 2) have acquired fluoroquinolone resistance. cc4821 was recently prevalent among carriage isolates in men who have sex with men in New York City (USA). Genome-level population studies have thus far been limited to Chinese isolates. The aim of the present study was to build upon these with an extended panel of international cc4821 isolates. METHODS: Genomes of isolates from Asia (1972 to 2017), Europe (2011 to 2018), North America (2007), and South America (2014) were sequenced or obtained from the PubMLST Neisseria database. Core genome comparisons were performed in PubMLST. RESULTS: Four lineages were identified. Western isolates formed a distinct, mainly serogroup B sublineage with alleles associated with fluoroquinolone susceptibility (MIC <0.03 mg/L) and reduced penicillin susceptibility (MIC 0.094 to 1 mg/L). A third of these were from anogenital sites in men who have sex with men and had unique denitrification gene alleles. Generally 4CMenB vaccine strain coverage was reliant on strain-specific NHBA peptides. DISCUSSION: The previously identified cc4821 group 2 was resolved into three separate lineages. Clustering of western isolates was surprising given the overall diversity of cc4821. Possible association of this cluster with the anogenital niche is worthy of monitoring given concerns surrounding antibiotic resistance and potential subcapsular vaccine escape.

Streptococcus equi subsp. equi meningitis, septicemia and subdural empyema in a child.

Streptococcus equi subsp. equi is a group C ß-hemolytic streptococcus, and is an invasive pathogen with a very restricted host, causing the equine infection known as 'strangles'. It is a poor colonizer in horses, preferentially causing invasion and infection, compared with its ancestor Streptococcus equi subsp. zooepidemicus, which is considered an opportunistic commensal of the equine upper respiratory tract. In humans, S. equi subsp. equi causes invasive infections in immunocompromised hosts, often following close contact with horses. Such infections are associated with a high mortality, as well as a poor neurological outcome in survivors. Beta-lactam antimicrobials form the mainstay of treatment, while neurosurgical intervention is occasionally required. We present the case of a 13-year old boy with systemic lupus erythematosus being treated with hydroxychloroquine, who presented with S. equi subsp. equi meningitis and sepsis after contact with a sick pony. Although he recovered fully following eight weeks of intravenous ceftriaxone and oral rifampin, the clinical course was complicated by subdural empyema requiring neurosurgical evacuation.

Clinically-diagnosed Mediterranean Spotted Fever in Malta.

BACKGROUND: Mediterranean Spotted Fever (MSF) is a tick-borne zoonosis caused by Rickettsia conorii which is endemic in Malta, an island in the South Mediterranean that is a popular tourist destination. Diagnosis is frequently based on clinical manifestations as laboratory results are often limited to a retrospective diagnosis. We describe the clinical presentation, diagnosis and treatment of children <16 years who presented with MSF from 2011 to 2016. METHOD: The demographics, clinical findings, laboratory results, management and outcome of all children hospitalised with suspected MSF based on the presence of fever and an eschar, were retrieved from their case notes. RESULTS: Over the five-year study period six children, aged between 17 months and 15 years, were diagnosed with MSF. All children had contact with ticks and the majority presented in summer. Laboratory results were non-specific and included elevated inflammatory markers, lymphocytosis/lymphopenia and hyponatraemia. Serological and molecular techniques were used for diagnosis. Response to clarithromycin or doxycycline was immediate. CONCLUSION: MSF should be included in the differential diagnosis of fever, rash and an eschar in children who travel to Malta. Despite advances in molecular diagnostics, clinical diagnosis remains important in the management of children with suspected MSF.

Leishmaniasis: diagnostic issues in Europe.

Leishmaniasis is a parasitic disease with clinical presentations that vary from asymptomatic infection to cutaneous, mucocutaneous or visceral disease. Recent epidemiological studies have shown an increased prevalence in Europe largely caused by an increase in international travel, difficulty eradicating leishmanial infection in AIDS patients, and the use of immunosuppressive medications. Clinical diagnosis may be challenging, and parasitological diagnosis entails the use of invasive procedures which may be unrevealing in the immunosuppressed. A number of less invasive tests for the detection of anti-leishmanial antibodies or leishmanial antigen are available but their sensitivity and specificity may vary with the infective species and results have to be interpreted in light of the clinical presentation. The availability of polymerase chain reaction assays amplifying leishmanial genetic material has been a major step forward in improving the diagnosis of leishmanial disease and the response to treatment.

Intrathoracic schwannoma with Horner syndrome.

Horner syndrome (HS) results from the interruption of the sympathetic pathway to the eye and face, and describes a collection of signs consisting of ipsilateral miosis, partial ptosis, anhidrosis and apparent enophthalmos. It is a clinical observation, and has a plethora of possible causes, ranging from the benign to the malignant. Involvement of the stellate ganglion on the sympathetic chain by malignant tumours of the lung is a well-recognised cause of HS. On the other hand, HS secondary to the excessive growth of a benign intrathoracic neoplasm is a very rare finding, with only a few cases described in the literature. Our patient was found to have such a diagnosis when he presented to medical attention with a 1-month history of cough that was associated with features of HS that he had ignored for the preceding 9 years.